Trovafloxacin is a known quinolone antibacterial of Formula I ##STR1##
Trovafloxacin has the chemical name: (1.alpha., 5.alpha., 6.alpha.)-7-(6-amino-3-azabicyclo[3.1. 0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyr idine-3-carboxylic acid.
Trovafloxacin, and salts and related derivatives thereof, and their antibacterial activities, are disclosed in U.S. Pat. Nos. 5,164,402; 5,229,396; 5,266,569; 5,391,763; and 5,763,454; and in International PCT Application Nos.
PCT/US95/07211 published as WO 96/39406 and IB/96/00756 published as WO 97/07800.
Trovafloxacin is available as a particular trovafloxacin acid addition salt, namely, trovafloxacin mesylate (TABLET), for oral administration and as alatrofloxacin (prodrug) mesylate for intravenous administration. (Physicians' Desk Reference (PDR), 53rd Ed., Medical Economics Co., Inc., Montvale, N.J., pages 2414-2421 (1999)).
Chemically, as discussed above, trovafloxacin mesylate, a fluoronaphthyridone related to the fluoroquinolone antibacterials, is (1.alpha., 5.alpha., 6.alpha.)-7-(6-amino-3-azabicyclo[3.1. 0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyr idine-3-carboxylic acid, monomethanesulfonate, of the Formula III ##STR2##
The TABLETS are available as 100 mg and 200 mg (trovafloxacin equivalent) blue, film-coated tablets, and also contain microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose and magnesium stearate. The TABLET coating is a mixture of hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide (TiO.sub.2), polyethylene glycol and FD&C blue #2 aluminum lake.
Oral dosage forms of pharmaceutical agents are generally preferred because they provide for easy, low-cost administration which generally encourages patient compliance. However, certain pharmaceutical agents, e.g., penicillin, ampicillin and erythromycin, exhibit the undesirable characteristic of bitter taste either during or immediately after oral administration which generally discourages patient compliance, particularly by pediatric patients.
Generally, sweetening agents such as sucrose, as well as flavoring agents, are added to such orally administered pharmaceutical compositions to mask such bitter taste and aftertaste. Other taste-masking agents are also known such as those described in U.S. Pat. No. 5,633,006 which discloses the use of an alkaline earth oxide in a liquid suspension pharmaceutical composition to mask the bitter taste and/or aftertaste of the bitter flavor of a bitter pharmaceutical agent. Alternatively, it is also known in the art to mask such bitterness by microencapsulating the unpleasant tasting active agent in a coating of ethyl cellulose, or other cellulose derivatives, to provide chewable taste-masked dosage forms.
As discussed above for certain pharmaceutical agents, solutions of trovafloxacin have also been identified as exhibiting the undesirable characteristic of bitter taste either during or immediately after oral administration. The TABLETS contain a salt of trovafloxacin, rather than a trovafloxacin zwitterion, and are suitably buffered to overcome such taste issues; however, tablets are not always the preferred dosage form, e.g., for pediatric patients, and for patients who are unable to swallow tablets.
This invention overcomes the taste issues associated with such solutions of trovafloxacin by providing liquid suspensions comprising novel trovafloxacin zwitterionic crystals which, by virtue, in part, of their unexpected physical and chemical stabilities, enable the preparation of substantially homogenous suspensions. The provision of such substantially homogenous suspensions enable accurate dosing.
Furthermore, the provision of easily pourable homogeneous suspensions also facilitates oral administration since, for example, no other fluid need be consumed simultaneously as is typically done with a tablet dosage form. Moreover, a certain population of patients, specifically pediatric patients, are generally more receptive to a fluid that they can see and swallow, or mix into food (where suitable), versus a tablet or a needle. Further yet, the health care provider, e.g., parent or physician, administering the medicine to a pediatric patient in the form of a liquid lessens both choking concerns (with respect to a tablet) and the dangers of handling a needle and syringe (with respect to an injection). Also, administration to large numbers of patients at once is easier, e.g., no fluid to wash down the tablet is necessary, and generates less waste, e.g., packaging of a suspension versus individual sterile syringes and needles for each patient.
While this invention does not intend to preclude the utility of dissolving a TABLET in a suitable pharmaceutically acceptable buffer, and the oral administration thereof; nonetheless, the liquid suspension pharmaceutical compositions of this invention provide the advantage of being ready for immediate administration as supplied. Moreover, because of the aforementioned physical and chemical properties of the novel trovafloxacin zwitterionic crystals comprising the suspensions of this invention, these suspensions, unlike suspensions in general, resuspend very quickly upon shaking, and resettle very slowly, which collectively allow for desirable homogeneity over a period of time suitable for oral administration.
A novel crystal form of a salt of trovafloxacin, i.e., trovafloxacin mesylate, methods of using the compound for the treatment of bacterial infections in mammals, especially humans, and pharmaceutical compositions comprising the compound, are disclosed in the aforementioned U.S. Pat. No. 5,763,454.
In contrast, novel trovafloxacin zwitterionic (versus salt) crystal forms are disclosed in the aforementioned WO 97/07800 of Formula II ##STR3##
selected from the group consisting of its crystalline non-hygroscopic (polymorph PI) and hygroscopic (polymorph PII) polymorphs and a pentahydrate, methods for their preparation, e.g., from a metastable form of trovafloxacin zwitterion (a needle form), and methods for treating bacterial infections in mammals by administering said compounds, e.g., as a suspension. A TABLET, dissolved in a suitable aqueous buffer, e.g., sodium bicarbonate, contains crystals of the needle form.
This invention provides additional novel trovafloxacin zwitterionic crystals, specifically a blade form and both a four-sided and a six-sided lath form, with the six-sided lath form being preferable. The aforementioned known needle form, as well as the novel blade and four-sided laths, all convert in an aqueous medium, over various periods of time, into the novel six-sided laths. This invention also provides novel processes for preparing the blade and lath crystals of this invention from the aforementioned known needle form. This invention further provides novel processes for converting between the blade and lath forms. Further, the crystals of the needle form, prepared from dissolving a TABLET in a suitable aqueous buffer, will convert over time to the six-sided lath form.
The oral administration of suspensions comprising these novel trovafloxacin zwitterionic crystals results in no appreciable bitter taste or aftertaste. In addition, once resuspended, these crystals tend to remain in suspension rather than settle out, which enables more accurate dosing. Moreover, the suspensions of this invention provide a more desirable dosage form for certain patients, e.g., children and the elderly.
This invention also provides methods for treating bacterial infections by administering such crystals or suspensions comprising such crystals.